Insulin Metabolism in Brain and Periphery: We have replicated our prior finding that medication-free patients with major depression (MDD) in the depressed phase are insulin resistant, have increased plasma glucose levels are in a proinflammatory state, and are dyslipidemic. These abnormalities normalized in remitted premenopausal medication-free women with major depression. These data are of interest in the light of recent evidence that chronic stressors such as overfeeding produce insulin resistance and inflammation first in brain, which precedes, and is a prerequisite for the impact of overfeeding on insulin resistance in the periphery. Recent data indicate that central insulin activity, though largely unrelated to glucose transport, significantly impacts glutamate metabolism, neuroplasticity, lesarning, and memory Surprisingly, abnormalities in peripheral insulin metabolism and lipid status remained present in remitted premenopausal women on SSRI treatment, despite their resolution in medication-free remitted patients. These data suggest that SSRIs per se have adverse effects on insulin and glucose metabolism and on the lipid profile. These data are of interest in the light of recent data that chronic stressors such as overfeeding that produce insulin resistance and inflammation first in the brain, which precedes, and is a prerequisite, for the impact of overfeeding on insulin resistance in the periphery. Thus, clinicians should potentially not be lulled into concluding that successfully treated patients, especially on SSRIs, have reslution of systemic stigmata, and that further interventions may be required. Inflammation in the Brain and Periphery: The central insulin resistance that precedes peripheral insulin resistance requires the activation of the innate inmmune mediator nF-kB in brain. This form of neuroinflammation is unique, in that it is a CNS inflammatory response that is limited only to the neuron, which both produces and reacts to the inflammatory stimulus. Other neuroinflammatory processes classically involve the synthesis of inflammatory mediators from adjacent glial cells that are released to bind to neuronal cell surface receptors. This intraneuronal CNS inflammatory process is generally associated with the uncoupled protein response (UPR), which occurs in the context of excessive demands upon neurons for protein synthesis, such as those that occur during overfeeding. We plan to determine the extent to which repeated social stress in mice is associated with the automediated inflammatory response of hippocampal neurons to another form of hyperstimulation, namely repeated social stress in mice. It should be noted that the uncoupled protein response occurs during glutamate-induced neuronal toxicity. In the periphery, inflammation is also closely linked with insulin resistance. Thus, we found that the peripheral insulin resistance, due, at least in part, to a preceding centrally-occurring insulin resistance, is also associated with innate immune activation, associated with an extensive repertoire of significant abnormalities in the secretion of innate immune mediators such as C-reactive protein (CRP), serum amaloid A, complement 3c, a-aminoglycoprotein, pre-albumin, ceruluplasmin, and transferrin. In experimental and clinical contexts associated with neuroinflammation, the ppar gamma agonist piaglitazone, which sensitizes insulin receptors, exerts profound anti-inflammatory effects in the CNS and the periphery. This compound is a excellent candidate for treatment of metabolic and inflammatory components of major depression, appearing either de novo or in the context of SSRI administration. It would be of great interest of a compound that combats insulin resistance and inflammation also exerts antideporessant effects. Inflammation and Bone Mineral Density: We have previously reported that premenopausal women with major depression had significant increases in the incidence of pathologically reduced bone mineral density compared to matched body mass index controls, We replicated this finding in a separate group of premenopausal women. In both groups, the pattern of bone was unusual, with high bone mineral density loss in the hip than in the spine. In experimental animals, models of inflammatory-induced osteoporosis preferentially showed this pattern. In the past year we found that post-menopausal women with major depression have increased plasma CRP levels that correlated positively with a trend towards reduction in bone mineral density. The Potential Role of CRH in the Affective and Systemic Manifestations of Major Depression: It is highly unlikely that any single mediator is responsible for initiating the syndrome of melancholic depression, associated with anxiety, HPA axis and SNS activations, and inhibition of neurovegetative functions such as food intake and sleep. We will test the hypothesis that the CRHR1 receptor is a target that can be successfully modified in the service of the resolution of both the affective and systemic manifestations of MDD PUBLIC HEALTH IMPLICATIONS OF THESE DATA: 1. The fact that SSRIs themselves produce insulin resistance and dyslipidemia despite successful resolution of depression raises the disturbing possibility that the life-shortening systemic manifestations in MDD may not resolve in the context of remissions induced by SSRIs. Thus, treatment with SSRIs should potentially be accompanied by an agent that improves insulin sensitivity and exerts anti-inflammatory effects. 2. The presence of insulin resistance and dyslipidemia seen here in medication free depressed patients and in recovered patients with major depression is of a magnitude sufficient to result in a significant increase in ten year overall mortality. 3. Our pathophysiologic data indicate that a trial of piaglitazone could ameliorate both the insulin resistance and inflammation associated with major depression or SSRI-induced remission of depression, thus ameliorating both central and peripheral manifestations of MDD. This compound is currently available for treatment of type II diabetes and is in clinical trials for the treatment of neurodegenerative disorders such as Alzheimer's disease,Parkinson's disease, and Huntington's chorea. 4. Premenopausal women have a loss in bone mineral density in a patter that suggests an inflammatory component in its pathophysiology. Our data indicate that given a prevalence of major depression in the 134 million US women between the ages of 21 and 45 years of approximately 16%, we estimate that nearly 4 million women with MDD may have undetected deficits in bone mineral density. We now demonstrate that post-menopausal women with major depression have losses of bone mineral density that significantly correlated with plasma levels of the inflammatory mediator CRP 5. We plan studies to determine if chronic social stress in mice produce the unique form of neuron-based inflammation in the hippocampus sseen in the hypothalamus in the context of overfeeding, in association with the uncoupled protein response. This would represent a novel form of neuroimflammation in MDD that could be targeted with agents not currently used in the treatment of MDD. 6. The availability of a single compound such as antalarmin that could rapidly ameliorate the affective and systemic maanifestations of MDD would be extremely valuable given the incidence of MDD and the failure rate of availabler antidepressant medications. Data in experimental animals suggest that antalarmin may have signioficant therapeutic effects in alcohol abuse and in proinflammatory states such as Crohn's disease.